Although arsenic is acknowledged to have a co-carcinogenic effect with solar ultraviolet (UV) radiation for skin tumor induction in mice, its action at the cellular and molecular level is not well understood. Our data shows that arsenite inhibits UV-induced cell apoptosis in mouse epidermal CI41 cells. Apoptosis plays an essential role as a protective mechanism against neoplastic development in the organism by eliminating genetically damaged cells. Thus, suppression of apoptosis is thought to contribute to tumorigenesis. Our data also demonstrate that arsenite induces activation of phosphatidylinositol 3-kinase (PI-3K) and nuclear factor-kB (NFkB), and has a synergistic effect with UVB on NFkB activation in mouse epidermal CI41 cells. Considering the important role of PI-3K/Akt/p70S6k and NFkB in the protection of cells from apoptosis, the main hypothesis of this proposal is that activation of PI-3K/Akt/p70S6k and/or NFkB plays an essential role in the arsenite protection of mouse skin epidermal cells from UV-induced apoptosis. We will investigate this issue in accordance with the following specific aims: 1) To identify the signaling pathway and its downstream gene implicated in arsenite protection of mouse skin cells from UV-induced cell apoptosis in vitro. 2) To determine the effect of arsenite on UV-induced activation of Akt, NFkB, and COX-2 expression in vivo. 3) To test whether arsenite is able to inhibit UV-induced apoptosis and whether NFkB activation is required for this inhibition in vivo. The significance of this application is that the results derived from these proposed studies will greatly facilitate the understanding of the molecular mechanisms of co-carcinogenesis of arsenite with UV radiation in mouse skin, which will help to understand cancer development caused by arsenite in human skin. A better understanding of molecular mechanisms of cancer development caused by arsenite in vitro and in vivo will provide valuable information to help design more effective agents for prevention and therapy of cancers caused by arsenite. Such agents may interfere with signaling pathways leading to inhibition of cell apoptosis. We believe that the proposed contribution of the anti-apoptotic effect of arsenite responsible for arsenite skin co-carcinogenic effects with UV radiation is novel and the integrated mechanistic studies in transgenic animal models and cell culture systems are strengths.